Induction of leukemic stem cell differentiation by aryl hydrocarbon receptor agonist and synergy with gilteritinib in FLT3-ITD + acute myeloid leukemia

Abstract

Leukemic stem cells (LSCs) are a major cause of treatment failure and recurrence of acute myeloid leukemia (AML). Targeting LSC is essential to developing a potential cure for patients with relapsed/refractory AML. Here we investigated the effect of aryl hydrocarbon receptor (AhR) signaling on AML stem/progenitor proportion and examined the combined effect of AhR agonist and tyrosine kinase inhibitor. The AhR agonist, 6-formylindolo[3,2-b]carbazole (FICZ), significantly decreased the LSC proportion and clonogenicity and increased differentiation markers in AML primary cells. Synergistic/additive effects of FICZ and gilteritinib, FMS-like tyrosine kinase 3 (FLT3) inhibitor, were confirmed in AML cells with FLT3-ITD. We present evidence that combination of both agents inhibits FLT3 downstream molecules and degrades clonogenicity. Collectively, our results suggest that FICZ not only compels LSC differentiation, but also enhances the efficacy of gilteritinib when combined. Clinical application of this combined approach may pave a new therapeutic strategy for patients with FLT3 mutated AML.

Keywords: Acute myeloid leukemia; FMS-like tyrosine kinase 3; aryl hydrocarbon receptor; combination treatment; differentiation; leukemic stem cell.